Leukotrienes participate in inflammatory reactions, exhibit chemotactic activities, stimulate lysosomal enzyme release and act as important factors in the intermediate hypersensitivity reaction. Leukotrienes are metabolic products of metabolism of arachidonic acid (AA) by lipoxygenase enzymes with the most significant leukotrienes being LTB.sub.4, LTC.sub.4, LTD.sub.4 and LTE.sub.4. The latter three leukotrienes are incorporated in the substance known as SRS or SRS-A, the slow-reacting substance of anaphylaxis [J. Immun. 215, 115-118 (1980), Biochem. Biophys. Res. Comm. 93, 1121-1126(1980)]. By another metabolic pathway, arachidonic acid is metabolized by cyclooxygenase enzymes to prostaglandins and thromboxanes.
Leukotrienes LTC.sub.4 and LTD.sub.4 are potent bronchoconstrictors of the human bronchi [Dahlen et al., Nature 288,484-486 (1980) and Piper, Int. Arch. Appl, Immunology 76, Suppl. 1, 43 (1985)] which stimulate the release of mucus from airways in vitro [Macom et al., Am. Rev. Resp. Dis. 126, 449 (1982)], are potent vasodilators in skin [Bisgaard et al., Prostaglandins 23, 797 (1982)], and produce a wheal and flare response [Camp et al., Brit. J. Pharmacol. 80 497 (1983)]. The nonpeptide leukotriene LTB.sub.4 is a powerful chemotactic factor for leukocytes [A. S. Ford - Hutchinson, J. Royal Soc. Med. 74, 831-883 (1981)], which stimulates cell accumulation and affects vascular smooth muscle [Bray, Brit. Med. Bull. 39, 249 (1983)]. The activity of leukotrienes as mediators of inflammation and hypersensitivity is extensively reviewed [Bailey and Casey, Ann. Reports Med. Chem. 17, 203-217 (1982) and Bray, Agents and Actions 19, 87 (1986) and Masamune and Melvin, Ann. Reports Med. Chem. 24, 71 (1989)].
There is also evidence that products of the cyclooxygenase/lipoxygenase pathways play key roles in both the pathogenesis of gastric mucosal damage due to extracellular (gastric and intestinal contents, microorganisms, and the like) or intracellular (ischemia, viruses, etc.) agents, as well as in cytoprotection against such damage. Thus, on the one hand prostaglandins exert a cytoprotective effect on the gastric mucosa [see Robert, Gastroenterology, 77, 761-767 (1979)] and this action of the prostaglandins, especially of the E series, is considered to be of importance in the treatment of gastrointestinal ulceration [see Isselbacher, Drugs, 33 (suppl.), 38-46 (1987)]. On the other hand, ex vivo experiments have shown that gastric mucosal tissue from ethanol-pretreated rats is capable of LTC.sub.4 generation and that this LTC.sub.4 production is quantitatively related to the severity of the ethanol damage [see Lange et al., Naunyn-Schmiedeberg's Arch, Pharmacol. Suppl., 330, R27, (1985)]. It has also been demonstrated that LTC.sub.4 can induce vasoconstriction in both venous and arteriolar vessels in the rat submucosa [see Whittle, IUPHAR Ninth Int. Cong. of Pharmac., S30-2, London, England (1984)]. This is significant since ethanol-induced lesion formation in gastric mucosa may be multifactorial with, for example, stasis of gastric blood flow contributing significantly to the development of the hemorrhagic necrotic aspects of the tissue injury [see Guth et al., Gastroenterology, 87, 1083-90 (1984)]. Moreover, in the anesthetized cat, exogenous LTD.sub.4 evokes both increased pepsin secretion and decreased transgastric potential [Pendleton et al., Eur. J. Pharmacol., 125, 297-99 (1986)]. A particularly significant recent finding in this regard is that 5-lipoxygenase inhibitors and some leukotriene antagonists protect the gastric mucosa against lesions induced by the oral or parenteral administration of most nonsteroidal antiinflammatory drugs [see Rainsford, Agents and Actions, 21, 316-19 (1987)]. Accordingly, a significant body of evidence implicates the involvement of lipoxygenase products in the development of pathological features associated with gastric mucosal lesions, such as for example those induced by ethanol exposure and administration of non-steroidal anti-inflammatory drugs. Thus, compounds which inhibit the biological effects of leukotrienes and/or which control the biosynthesis of these substances, as by inhibiting 5-lipoxygenase, are considered to be of value as cytoprotective agents.
Accordingly, the biological activity of the leukotrienes and SRS's, and of lipoxygenase as the enzyme leading to the metabolism of AA to leukotrienes, indicates that a rational approach to drug therapy to prevent, remove or ameliorate the symptoms of allergies, anaphylaxis, asthma and inflammation and for gastric cytoprotection must focus on either blocking the release of mediators of these conditions or antagonizing their effects. Thus compounds, which inhibit the biological effects of the leukotrienes and SRS's and/or which control the biosynthesis of these substances, as by inhibiting lipoxygenase, are considered to be of value in treating such conditions as allergic bronchial asthma, allergic rhinitis, as well as in other immediate hypersensitivity reactions and in providing gastric cytoprotection.
Compounds of this invention inhibit lipoxygenase and antagonize products of the lipoxygenase pathway and thus are useful as antiinflammatory and anti-allergic agents. Compounds of this invention are expected to have gastric cytoprotective activity.
Atherosclerosis, the underlying disease implicated in myocardial infarction and strokes, is a complex pathologic process involving the intimal layer of the arteries. The earliest lesion of atherosclerosis is development of the fatty streak lesions which contain lipid-laden macrophages and lipid-laden smooth muscle cells. Macrophages do not take up native low density lipoprotein (LDL) but do take up modified, i.e., acetylated LDL or oxidized LDL via acetyl-LDL or "scavenger" receptors to form the foam cells of atherosclerotic plaque. Free radial oxidation, i.e., lipid peroxidation, has been shown to be involved in the alteration of LDL by endothelial cells. Arterial smooth muscle cells generate superoxide and oxidize LDL in the presence of micromolar concentrations of Cu.sup.+2 or Fe.sup.+2. The way LDL can be modified by endothelial cells can be mimicked in vitro by incubation of the lipoprotein in the presence of CuCl.sub.2. Probucol, an antihyperlipidemic agent, also inhibits both cell mediated and Cu.sup.+2 mediated oxidative modification of LDL, and was shown to inhibit the formation of atherosclerotic lesions in WHHL rabbits [Reaven et al., Arteriosclerosis and Thrombosis 12(3), 318-324 (1992), Steinberg, The Amer. J. of Cardiology 57, 16H-21H (1986), Carew. Schwenke and Steinberg, Proc. Natl. Acad. Sci. 84, 7725-7729 (1987) and Nagano et al., Arteriosclerosis 9 (4), 453-461 (1989)]. Thus in vitro inhibition of Cu.sup.+2 catalyzed oxidation of LDL is indicative of antiatherosclerotic utility.
Compounds of this invention inhibit in vitro the copper-induced peroxidation of LDL and thus are useful in the treatment or prevention of arteriosclerosis.
Lipoxygenase inhibiting compounds of the formula: ##STR2## wherein R.sup.1 is amino or methyl, R.sup.2 is C.sub.1 -C.sub.2 alkyl, R.sup.3 is selected from hydrogen, halogen, and trihalomethyl; R.sup.4 is hydrogen, halogen, trihalomethyl, C.sub.1 -C.sub.4 alkoxy or C.sub.1 -C.sub.4 alkyl; and M is hydrogen, a pharmaceutically acceptable cation, aroyl or C.sub.1 -C.sub.6 alkoyl are disclosed in EP 279281 A2. EP 0384594 A1 discloses antiinflammatory 5-lipoxygenase inhibitors of the formula: ##STR3## wherein R.sup.1 and R.sup.2 are selected from H and C.sub.1 -C.sub.4 alkyl independently and the 4-halophenoxy moiety can be attached to the phenyl ring at either the 3 or 4 position.
The PCT patent WO 90/12008 (equivalent to U.S. Pat. No. 5,185,363) discloses lipoxygenase inhibiting compounds of the formula: ##STR4## wherein M is, among other choices, hydrogen or a pharmaceutically acceptable cation; Z is O or S; X is a straight or branched C.sub.1 -C.sub.6 alkylene or C.sub.2 -C.sub.6 alkenylene group optionally substituted by hydroxy, halogen, cyano, alkoxy, aminocarbonyl, carboxy and alkoxycarbonyl; R.sup.1 and R.sup.2 are independently hydrogen, hydroxy, or C.sub.1 -C.sub.6 alkyl optionally substituted by hydroxy, halogen, cyano, alkoxy, etc., with a proviso that both R.sup.1 and R.sub.2 cannot hydroxy; and R.sub.3 can be phenyl, naphthyl or thienyl optionally substituted by a variety of substituents including carbocyclic or heterocyclic arylalkoxy groups optionally substituted by halogen, nitro, cyano, alkyl, alkoxy or halosubstituted alkyl wherein the heterocyclic aryl moiety is defined as a 5 to 6 membered ring containing one N, S, or O atom or a N and O or a N and S or three N atoms and further stipulates that the 5 to 6 membered heterocyclicaryl moiety may be fused with a phenyl ring to form a benzo-fused heterocycle. The PCT application WO 92/03425 (equivalent to U.S. Pat. No. 5,334,604) discloses compounds that are intermediates to antidiabetic compounds having the formula: ##STR5## wherein n is 0 or 1, R is hydrogen or C.sub.1 -C.sub.3 alkyl, R.sup.3 is one of C.sub.1 -C.sub.9 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl, naphthyl, furyl, benzofuryl or thienyl optionally substituted with one or two groups selected from C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, C.sub.1-C.sub.3 alkoxycarbonyl, trifluoromethyl, fluoro or chloro; R.sup.6 is hydrogen, C.sub.1 -C.sub.9 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl, naphthyl, furyl, benzofuryl or thienyl and R.sup.7 is hydrogen or a conventional protecting group. N-Aryl-N-hydroxy ureas, formamides and alkylamides having previously been disclosed to have lipoxygenase inhibiting activity, are disclosed in WO 92/03130 as having anti-atherosclerotic activity and have the formula: EQU Ar--Y--Q
wherein Ar is heteroaromatic, naphthyl, tetrahydronaphthyl, phenyl or phenyl substituted by phenyl, naphthyl or a heteroaromatic group; Y is C.sub.1 -C.sub.10 alkylene or C.sub.2 -C.sub.10 alkenelene and Q is ##STR6## where R.sup.1 is H, C.sub.1 -C.sub.4 alkyl or an Ar group and R.sup.2 is H, C.sub.1 -C.sub.4 alkyl, amino, mono or dialkylamino, cycloalkylamino, cycloalkylalkylamino, anilino, N-alkylanilino or an Ar group.